Osteoporosis affects over 44 million Americans leading to direct annual expenditures in excess of $20 billion. Measuring the success of bone-sparing therapies requires not only sensitive tests but also convenient patient procedures since many osteoporosis sufferers are elderly. In the present study, we propose to test the utility of saliva, an easily collected biofluid, to measure changes in bone turnover in a group of peri-menopausal women who are participating in a randomized, double-blind, placebo-controlled 5-year study conducted as part of the Kronos Early Estrogen Prevention Study (KEEPS). Mayo Clinic is one of [unreadable] 8 participating centers nationally. The primary purpose of KEEPS is to study the effect of estrogen [unreadable] formulations on atherosclerosis. Fortuitously, bone turnover marker levels in serum and bone mineral density values will also be obtained meaning that KEEPS offers an extraordinary opportunity to investigate saliva. The central hypothesis of this application is that host derived bone-specific proteins present in human saliva will serve as biomarkers of systemic bone turnover and bone mineral density. The rationale for our proposal is that if levels of bone turnover markers in saliva correlate with levels in serum and/or BMD, then saliva, an easily collected biofluid, can be used to monitor systemic bone turnover. We are particularly well prepared to undertake this research because: (1) we have demonstrated that the bone turnover markers can be detected by conventional enzyme-linked immunoassays in human saliva; and (2) the KEEPS infrastructure ensures a rigorous clinical research environment. We will test our hypothesis by pursuing the [unreadable] following two specific aims: [unreadable] 1) Determine whether salivary bone turnover marker levels correlate with serum levels in a controlled clinical trial population. The working hypothesis is that levels of biomarkers in saliva are representative of levels of the same biomarkers in serum. [unreadable] 2) Determine the relationship between changes in salivary bone turnover marker levels and changes in BMD in a controlled clinical trial population. The working hypothesis is that bone turnover as measured by changes in levels of salivary biomarkers in the saliva of subjects receiving MHT is associated with increase in BMD when compared to subjects receiving placebo therapy. [unreadable] This ancillary study application addresses a key directive outlined by the NIDCR Panel on Genomics and Proteomics of Oral, Dental and Craniofacial Diseases which stressed the need to investigate saliva as a diagnostic tool. We anticipate that our results will identify how salivary biomarkers can be used to assess the osseo-status of patients with, or at risk for, osteoporosis. [unreadable] [unreadable] [unreadable] [unreadable]